Complex of gadolinium and a chelating ligand derived from a diastereoisomerically enriched PCTA and preparation and purification process

Abstract

The present invention relates to a complex of formula (II) constituted of at least 90% of a diastereoisomeric excess comprising a mixture of isomers II-RRR and II-SSS of formulae: The present invention also relates to a process for preparing and purifying said complex of formula (II), and also to a composition comprising said complex.

The invention claimed is: 
     
       1. A method of medical imaging, the method comprising administering to a subject in need thereof a composition comprising:
 1) a complex of formula (II) below: 
 
       
         
           
           
               
               
           
         
         having a diastereoisomeric excess of at least 80% of a mixture of isomers II-RRR and II-SSS of formulae: 
       
       
         
           
           
               
               
           
         
       
       and
 2) a free macrocyclic ligand, 
 wherein the composition has a concentration of free gadolinium of less than 1 ppm (m/v), and 
 wherein the composition comprises from 0.002 to 0.4 mol/mol % of free macrocyclic ligand relative to the complex of formula (II). 
 
     
     
       2. The method of  claim 1 , wherein the composition comprises from 0.01 to 0.3 mol/mol % of free macrocyclic ligand relative to the complex of formula (II). 
     
     
       3. The method of  claim 1 , wherein the degree of purity of the complex of formula (II) is greater than 90% evaluated by chromatography. 
     
     
       4. The method of  claim 1 , wherein the degree of purity of the complex of formula (II) is greater than 95% evaluated by chromatography. 
     
     
       5. The method of  claim 1 , wherein the degree of purity of the complex of formula (II) is greater than 97% evaluated by chromatography. 
     
     
       6. The method of  claim 1 , wherein the isomers II-RRR and II-SSS are present in the mixture in a ratio of between 60/40 and 40/60. 
     
     
       7. The method of  claim 1 , wherein the composition has a concentration of complex of formula (II) of between 0.01 and 1.5 mol·L −1 . 
     
     
       8. The method of  claim 1 , wherein the free macrocyclic ligand is selected from the group constituted of DOTA, NOTA, DO3A, BT-DO3A, HP-DO3A, PCTA, DOTA-GA and derivatives thereof. 
     
     
       9. The method of  claim 1 , wherein the pH of the composition is between 4.5 and 8.5. 
     
     
       10. The method of  claim 1 , wherein the composition further comprises a buffer selected from the group consisting of lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate, Tris (Tris(hydroxymethyl)aminomethane), HEPES (2-[4-(2-hydroxyethyl)-1-piperazine]ethanesulfonic acid), MES (2-morpholinoethanesulfonic acid) buffers and mixtures thereof. 
     
     
       11. The method of  claim 3 , wherein the free macrocyclic ligand is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). 
     
     
       12. The method of  claim 11 , wherein the composition has a concentration of complex of formula (II) of between 0.3 and 0.6 mol·L −1 . 
     
     
       13. The method of  claim 11 , wherein the composition further comprises a buffer being Tris (Tris(hydroxymethyl)aminomethane) and has a pH between 6.5 and 8.